The CDK1 Inhibitory Kinase MYT1 in DNA Damage Checkpoint Recovery
Total Page:16
File Type:pdf, Size:1020Kb
Load more
Recommended publications
-
Proteomic Based Approaches for Differentiating Tumor Subtypes
Proteomic Based Approaches for Differentiating Tumor Subtypes DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Linan Wang Graduate Program in Integrated Biomedical Science Program The Ohio State University 2017 Dissertation Committee: Michael Alan Freitas, PhD Advisor Charles Lawrence Hitchcock, MD/PhD Kun Huang, PhD Mark Robert Parthun, PhD Copyright by Linan Wang 2017 Abstract In medicine, successful patient treatment relies on early and accurate diagnosis. Following diagnosis disease specific and effective treatments are necessary, targeting affected cells while sparing normal tissue. While past studies have focused on genomics, the importance of transcriptomics and proteomics is increasingly understood. Proteomics, the study of proteins, will be the focus of this dissertation. Proteomics provide insight in the post transcriptional and translational regulation of proteins, information not available through the study of DNA and RNA alone. These effects play an important role in protein quantity and physiological function. It is well established that changes in protein homeostasis are associated with disease conditions, hence providing the grounds for biomarker discovery. It has been shown that if homeostasis can be restored, disease conditions can be reversed, further emphasizing the role of proteomics in therapeutic target discovery. Chapter 1 highlights the importance of proteomics in the field of biomedical research with an emphasis on clinical translational sciences in moving discoveries from bench to bedside. Chapters 2 of this dissertation describe the development of methodology for the study of archived clinical biopsy samples. Following biopsy, patient tissue is preserved with formalin fixation and paraffin embedding (FFPE) and archived. -
DNA Damage Checkpoint Dynamics Drive Cell Cycle Phase Transitions
bioRxiv preprint doi: https://doi.org/10.1101/137307; this version posted August 4, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. DNA damage checkpoint dynamics drive cell cycle phase transitions Hui Xiao Chao1,2, Cere E. Poovey1, Ashley A. Privette1, Gavin D. Grant3,4, Hui Yan Chao1, Jeanette G. Cook3,4, and Jeremy E. Purvis1,2,4,† 1Department of Genetics 2Curriculum for Bioinformatics and Computational Biology 3Department of Biochemistry and Biophysics 4Lineberger Comprehensive Cancer Center University of North Carolina, Chapel Hill 120 Mason Farm Road Chapel Hill, NC 27599-7264 †Corresponding Author: Jeremy Purvis Genetic Medicine Building 5061, CB#7264 120 Mason Farm Road Chapel Hill, NC 27599-7264 [email protected] ABSTRACT DNA damage checkpoints are cellular mechanisms that protect the integrity of the genome during cell cycle progression. In response to genotoxic stress, these checkpoints halt cell cycle progression until the damage is repaired, allowing cells enough time to recover from damage before resuming normal proliferation. Here, we investigate the temporal dynamics of DNA damage checkpoints in individual proliferating cells by observing cell cycle phase transitions following acute DNA damage. We find that in gap phases (G1 and G2), DNA damage triggers an abrupt halt to cell cycle progression in which the duration of arrest correlates with the severity of damage. However, cells that have already progressed beyond a proposed “commitment point” within a given cell cycle phase readily transition to the next phase, revealing a relaxation of checkpoint stringency during later stages of certain cell cycle phases. -
Hidden Targets in RAF Signalling Pathways to Block Oncogenic RAS Signalling
G C A T T A C G G C A T genes Review Hidden Targets in RAF Signalling Pathways to Block Oncogenic RAS Signalling Aoife A. Nolan 1, Nourhan K. Aboud 1, Walter Kolch 1,2,* and David Matallanas 1,* 1 Systems Biology Ireland, School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland; [email protected] (A.A.N.); [email protected] (N.K.A.) 2 Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland * Correspondence: [email protected] (W.K.); [email protected] (D.M.) Abstract: Oncogenic RAS (Rat sarcoma) mutations drive more than half of human cancers, and RAS inhibition is the holy grail of oncology. Thirty years of relentless efforts and harsh disappointments have taught us about the intricacies of oncogenic RAS signalling that allow us to now get a pharma- cological grip on this elusive protein. The inhibition of effector pathways, such as the RAF-MEK-ERK pathway, has largely proven disappointing. Thus far, most of these efforts were aimed at blocking the activation of ERK. Here, we discuss RAF-dependent pathways that are regulated through RAF functions independent of catalytic activity and their potential role as targets to block oncogenic RAS signalling. We focus on the now well documented roles of RAF kinase-independent functions in apoptosis, cell cycle progression and cell migration. Keywords: RAF kinase-independent; RAS; MST2; ASK; PLK; RHO-α; apoptosis; cell cycle; cancer therapy Citation: Nolan, A.A.; Aboud, N.K.; Kolch, W.; Matallanas, D. Hidden Targets in RAF Signalling Pathways to Block Oncogenic RAS Signalling. -
Cyclin-Dependent Kinases and P53 Pathways Are Activated Independently and Mediate Bax Activation in Neurons After DNA Damage
The Journal of Neuroscience, July 15, 2001, 21(14):5017–5026 Cyclin-Dependent Kinases and P53 Pathways Are Activated Independently and Mediate Bax Activation in Neurons after DNA Damage Erick J. Morris,1 Elizabeth Keramaris,2 Hardy J. Rideout,3 Ruth S. Slack,2 Nicholas J. Dyson,1 Leonidas Stefanis,3 and David S. Park2 1Massachusetts General Hospital Cancer Center, Laboratory of Molecular Oncology, Charlestown, Massachusetts 02129, 2Neuroscience Research Institute, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada, and 3Columbia University, New York, New York 10032 DNA damage has been implicated as one important initiator of ization, and DNA binding that result from DNA damage are not cell death in neuropathological conditions such as stroke. Ac- affected by the inhibition of CDK activity. Conversely, no de- cordingly, it is important to understand the signaling processes crease in retinoblastoma protein (pRb) phosphorylation was that control neuronal death induced by this stimulus. Previous observed in p53-deficient neurons that were treated with camp- evidence has shown that the death of embryonic cortical neu- tothecin. However, either p53 deficiency or the inhibition of rons treated with the DNA-damaging agent camptothecin is CDK activity alone inhibited Bax translocation, cytochrome c dependent on the tumor suppressor p53 and cyclin-dependent release, and caspase-3-like activation. Taken together, our re- kinase (CDK) activity and that the inhibition of either pathway sults indicate that p53 and CDK are activated independently alone leads to enhanced and prolonged survival. We presently and then act in concert to control Bax-mediated apoptosis. show that p53 and CDKs are activated independently on par- allel pathways. -
1 Tumor Suppressor PLK2 May Serve As a Biomarker in Triple-Negative Breast Cancer for Improved Response to PLK1 Therapeutics
bioRxiv preprint doi: https://doi.org/10.1101/2021.06.16.448722; this version posted June 16, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Tumor suppressor PLK2 may serve as a biomarker in triple-negative breast cancer for improved response to PLK1 therapeutics Yang Gao1, 2, 3, Elena B. Kabotyanski1, 2, Elizabeth Villegas7, Jonathan H. Shepherd8, Deanna Acosta1, 2, Clark Hamor1, 2, Tingting Sun2,4,5, Celina Montmeyor-Garcia9, Xiaping He8, Lacey E. Dobrolecki1, 2, 3, Thomas F. Westbrook2, 4, 5, Michael T. Lewis1, 2, 3, Susan G. Hilsenbeck2, 3, Xiang H.-F. Zhang1, 2, 3, 6, Charles M. Perou8 and Jeffrey M. Rosen1, 2 1Department of Molecular and Cellular Biology 2Dan L. Duncan Cancer Center 3Lester and Sue Smith Breast Center 4Department of Molecular and Human Genetics 5Verna & Marrs McLean Department of Biochemistry and Molecular Biology 6McNair Medical Institute Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA 7University of Houston-Downtown, Houston, TX 77002, USA 8The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA 9 Canadian Blood Services, Toronto, ON M5G 2M1, Canada Correspondence to Jeffrey M. Rosen (Mail Stop: BCM130, Room: BCM-M638a, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030. Office: 713-798-6210. Fax: 713-898-8012. Email: [email protected]) 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.06.16.448722; this version posted June 16, 2021. -
The Cryoelectron Microscopy Structure of the Human CDK-Activating Kinase
The cryoelectron microscopy structure of the human CDK-activating kinase Basil J. Grebera,b,1,2, Juan M. Perez-Bertoldic, Kif Limd, Anthony T. Iavaronee, Daniel B. Tosoa, and Eva Nogalesa,b,d,f,2 aCalifornia Institute for Quantitative Biosciences (QB3), University of California, Berkeley, CA 94720; bMolecular Biophysics and Integrative Bio-Imaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720; cBiophysics Graduate Group, University of California, Berkeley, CA 94720; dDepartment of Molecular and Cell Biology, University of California, Berkeley, CA 94720; eQB3/Chemistry Mass Spectrometry Facility, University of California, Berkeley, CA 94720; and fHoward Hughes Medical Institute, University of California, Berkeley, CA 94720 Edited by Seth A. Darst, Rockefeller University, New York, NY, and approved August 4, 2020 (received for review May 14, 2020) The human CDK-activating kinase (CAK), a complex composed of phosphoryl transfer (11). However, in addition to cyclin binding, cyclin-dependent kinase (CDK) 7, cyclin H, and MAT1, is a critical full activation of cell cycle CDKs requires phosphorylation of the regulator of transcription initiation and the cell cycle. It acts by T-loop (9, 12). In animal cells, these activating phosphorylations phosphorylating the C-terminal heptapeptide repeat domain of are carried out by CDK7 (13, 14), itself a cyclin-dependent ki- the RNA polymerase II (Pol II) subunit RPB1, which is an important nase whose activity depends on cyclin H (14). regulatory event in transcription initiation by Pol II, and it phos- In human and other metazoan cells, regulation of transcription phorylates the regulatory T-loop of CDKs that control cell cycle initiation by phosphorylation of the Pol II-CTD and phosphor- progression. -
Genome-Wide Association Study to Identify Genomic Regions And
www.nature.com/scientificreports OPEN Genome‑wide association study to identify genomic regions and positional candidate genes associated with male fertility in beef cattle H. Sweett1, P. A. S. Fonseca1, A. Suárez‑Vega1, A. Livernois1,2, F. Miglior1 & A. Cánovas1* Fertility plays a key role in the success of calf production, but there is evidence that reproductive efciency in beef cattle has decreased during the past half‑century worldwide. Therefore, identifying animals with superior fertility could signifcantly impact cow‑calf production efciency. The objective of this research was to identify candidate regions afecting bull fertility in beef cattle and positional candidate genes annotated within these regions. A GWAS using a weighted single‑step genomic BLUP approach was performed on 265 crossbred beef bulls to identify markers associated with scrotal circumference (SC) and sperm motility (SM). Eight windows containing 32 positional candidate genes and fve windows containing 28 positional candidate genes explained more than 1% of the genetic variance for SC and SM, respectively. These windows were selected to perform gene annotation, QTL enrichment, and functional analyses. Functional candidate gene prioritization analysis revealed 14 prioritized candidate genes for SC of which MAP3K1 and VIP were previously found to play roles in male fertility. A diferent set of 14 prioritized genes were identifed for SM and fve were previously identifed as regulators of male fertility (SOD2, TCP1, PACRG, SPEF2, PRLR). Signifcant enrichment results were identifed for fertility and body conformation QTLs within the candidate windows. Gene ontology enrichment analysis including biological processes, molecular functions, and cellular components revealed signifcant GO terms associated with male fertility. -
Metabolic Checkpoints in Cancer Cell Cycle
City University of New York (CUNY) CUNY Academic Works All Dissertations, Theses, and Capstone Projects Dissertations, Theses, and Capstone Projects 2-2014 Metabolic Checkpoints in Cancer Cell Cycle Mahesh Saqcena Graduate Center, City University of New York How does access to this work benefit ou?y Let us know! More information about this work at: https://academicworks.cuny.edu/gc_etds/106 Discover additional works at: https://academicworks.cuny.edu This work is made publicly available by the City University of New York (CUNY). Contact: [email protected] METABOLIC CHECKPOINTS IN CANCER CELL CYCLE By Mahesh Saqcena A dissertation submitted to the Graduate Faculty in Biochemistry in partial fulfillment of the requirements for the degree of Doctor of Philosophy, The City University of New York 2014 i 2014 Mahesh Saqcena All Rights Reserved ii This manuscript has been read and accepted for the Graduate Faculty in Biochemistry in satisfaction of the dissertation requirement for the degree of Doctor of Philosophy. Date Dr. David A. Foster (Chair of Examining Committee) Date Dr. Edward J. Kennelly (Executive Officer) Dr. Mitchell Goldfarb (Hunter College) Dr. Paul Feinstein (Hunter College) Dr. Richard Kolesnick (Sloan Kettering Institute) Dr. Frederick R. Cross (Rockefeller University) (Supervisory Committee) THE CITY UNIVERSITY OF NEW YORK iii Abstract METABOLIC CHECKPOINTS IN CANCER CELL CYCLE by Mahesh Saqcena Advisor: Dr. David A. Foster Growth factors (GFs) as well as nutrient sufficiency regulate cell division in metazoans. The vast majority of mutations that contribute to cancer are in genes that regulate progression through the G1 phase of the cell cycle. A key regulatory site in G1 is the growth factor-dependent Restriction Point (R), where cells get permissive signals to divide. -
Clinical Candidates Targeting the ATR–CHK1–WEE1 Axis in Cancer
cancers Review Clinical Candidates Targeting the ATR–CHK1–WEE1 Axis in Cancer Lukas Gorecki 1 , Martin Andrs 1,2 and Jan Korabecny 1,* 1 Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic; [email protected] (L.G.); [email protected] (M.A.) 2 Laboratory of Cancer Cell Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic * Correspondence: [email protected]; Tel.: +420-495-833-447 Simple Summary: Selective killing of cancer cells is privileged mainstream in cancer treatment and targeted therapy represents the new tool with a potential to pursue this aim. It can also aid to overcome resistance of conventional chemo- or radio-therapy. Common mutations of cancer cells (defective G1 control) favor inhibiting intra-S and G2/M-checkpoints, which are regulated by ATR–CHK1–WEE1 pathway. The ATR–CHK1–WEE1 axis has produced several clinical candidates currently undergoing clinical trials in phase II. Clinical results from randomized trials by ATR and WEE1 inhibitors warrant ongoing clinical trials in phase III. Abstract: Selective killing of cancer cells while sparing healthy ones is the principle of the perfect cancer treatment and the primary aim of many oncologists, molecular biologists, and medicinal chemists. To achieve this goal, it is crucial to understand the molecular mechanisms that distinguish cancer cells from healthy ones. Accordingly, several clinical candidates that use particular mutations in cell-cycle progressions have been developed to kill cancer cells. As the majority of cancer cells have defects in G1 control, targeting the subsequent intra-S or G2/M checkpoints has also been extensively Citation: Gorecki, L.; Andrs, M.; pursued. -
The Involvement of Ubiquitination Machinery in Cell Cycle Regulation and Cancer Progression
International Journal of Molecular Sciences Review The Involvement of Ubiquitination Machinery in Cell Cycle Regulation and Cancer Progression Tingting Zou and Zhenghong Lin * School of Life Sciences, Chongqing University, Chongqing 401331, China; [email protected] * Correspondence: [email protected] Abstract: The cell cycle is a collection of events by which cellular components such as genetic materials and cytoplasmic components are accurately divided into two daughter cells. The cell cycle transition is primarily driven by the activation of cyclin-dependent kinases (CDKs), which activities are regulated by the ubiquitin-mediated proteolysis of key regulators such as cyclins, CDK inhibitors (CKIs), other kinases and phosphatases. Thus, the ubiquitin-proteasome system (UPS) plays a pivotal role in the regulation of the cell cycle progression via recognition, interaction, and ubiquitination or deubiquitination of key proteins. The illegitimate degradation of tumor suppressor or abnormally high accumulation of oncoproteins often results in deregulation of cell proliferation, genomic instability, and cancer occurrence. In this review, we demonstrate the diversity and complexity of the regulation of UPS machinery of the cell cycle. A profound understanding of the ubiquitination machinery will provide new insights into the regulation of the cell cycle transition, cancer treatment, and the development of anti-cancer drugs. Keywords: cell cycle regulation; CDKs; cyclins; CKIs; UPS; E3 ubiquitin ligases; Deubiquitinases (DUBs) Citation: Zou, T.; Lin, Z. The Involvement of Ubiquitination Machinery in Cell Cycle Regulation and Cancer Progression. 1. Introduction Int. J. Mol. Sci. 2021, 22, 5754. https://doi.org/10.3390/ijms22115754 The cell cycle is a ubiquitous, complex, and highly regulated process that is involved in the sequential events during which a cell duplicates its genetic materials, grows, and di- Academic Editors: Kwang-Hyun Bae vides into two daughter cells. -
Wee1 Rather Than Plk1 Is Inhibited by AZD1775 at Therapeutically Relevant Concentrations
cancers Article Wee1 Rather Than Plk1 Is Inhibited by AZD1775 at Therapeutically Relevant Concentrations Angela Flavia Serpico 1,2, Giuseppe D’Alterio 1,2, Cinzia Vetrei 1,2, Rosa Della Monica 1, Luca Nardella 1,2, Roberta Visconti 3 and Domenico Grieco 1,4,* 1 CEINGE Biotecnologie Avanzate, 80145 Naples, Italy; angelafl[email protected] (A.F.S.); [email protected] (G.D.); [email protected] (C.V.); [email protected] (R.D.M.); [email protected] (L.N.) 2 DMMBM, University of Naples “Federico II”, 80131 Naples, Italy 3 IEOS, CNR, 80131 Naples, Italy; [email protected] 4 Department of Pharmacy, University of Naples “Federico II”, 80131 Naples, Italy * Correspondence: [email protected] Received: 24 April 2019; Accepted: 10 June 2019; Published: 13 June 2019 Abstract: Wee1 kinase is an inhibitor of cyclin-dependent kinase (cdk)s, crucial cell cycle progression drivers. By phosphorylating cdk1 at tyrosine 15, Wee1 inhibits activation of cyclin B-cdk1 (Cdk1), preventing cells from entering mitosis with incompletely replicated or damaged DNA. Thus, inhibiting Wee1, alone or in combination with DNA damaging agents, can kill cancer cells by mitotic catastrophe, a tumor suppressive response that follows mitosis onset in the presence of under-replicated or damaged DNA. AZD1775, an orally available Wee1 inhibitor, has entered clinical trials for cancer treatment following this strategy, with promising results. Recently, however, AZD1775 has been shown to inhibit also the polo-like kinase homolog Plk1 in vitro, casting doubts on its mechanism of action. Here we asked whether, in the clinically relevant concentration range, AZD1775 inhibited Wee1 or Plk1 in transformed and non-transformed human cells. -
Transcription of Platelet-Derived Growth Factor Receptor a in Leydig Cells Involves Specificity Protein 1 and 3
125 Transcription of platelet-derived growth factor receptor a in Leydig cells involves specificity protein 1 and 3 Francis Bergeron1, Edward T Bagu1 and Jacques J Tremblay1,2 1Reproduction, Perinatal and Child Health, CHUQ Research Centre, CHUL Room T1-49, 2705 Laurier Boulevard, Que´bec, Que´bec, Canada G1V 4G2 2Department of Obstetrics and Gynecology, Faculty of Medicine, Centre for Research in Biology of Reproduction, Universite´ Laval, Que´bec, Que´bec, Canada G1V 0A6 (Correspondence should be addressed to J J Tremblay; Email: [email protected]) Abstract Platelet-derived growth factor (PDGF) A is secreted by Sertoli cells and acts on Leydig precursor cells, which express the receptor PDGFRA, triggering their differentiation into steroidogenically active Leydig cells. There is, however, no information regarding the molecular mechanisms that govern Pdgfra expression in Leydig cells. In this study, we isolated and characterized a 2.2 kb fragment of the rat Pdgfra 50-flanking sequence in the TM3 Leydig cell line, which endogenously expresses Pdgfra. A series of 50 progressive deletions of the Pdgfra promoter was generated and transfected in TM3 cells. Using this approach, two regions (K183/K154 and K154/K105), each conferring 46% of Pdgfra promoter activity, were identified. To better define the regulatory elements, trinucleotide mutations spanning the K154/K105 region were introduced by site-directed mutagenesis in the context of the K2.2kb Pdgfra promoter. Mutations that altered the TCCGAGGGAAAC sequence at K138 bp significantly decreased Pdgfra promoter activity in TM3 cells. Several proteins from TM3 nuclear extracts were found to bind to this G(C/A) motif in electromobility shift assay.